Atherosclerotic Plaque Components Research Articles

The Relationship Between Volumetric Plaque Components and Classical Cardiovascular Risk Factors and the Metabolic Syndrome: A 3-Vessel Coronary Artery Virtual Histology–Intravascular Ultrasound Analysis

The aim of this study was to analyze volumetric plaque composition of the coronary arterial tree according to the classical cardiovascular risk factors and metabolic syndrome (MS) using virtual histology-intravascular ultrasound (VH-IVUS). It remains unclear how the cardiovascular risk factors correlate with the histological components of coronary plaques. "Whole vessel" VH-IVUS analysis was performed in 189 vessels of 63 patients. The components of atherosclerotic plaques were classified as fibrous, fibrofatty, necrotic core (NC), and dense calcium. Quantitative assessment of these plaque components and the presence of VH-IVUS-derived thin-cap fibroatheroma in the coronary arterial trees were compared with cardiovascular risk factors. There was a significantly larger mean plaque-plus-media burden in patients with diabetes mellitus (DM) (47 ± 5% vs. 39 ± 7% in non-DM patients, p < 0.001) and MS (47 ± 4% vs. 39 ± 7% in non-MS patients, p < 0.001). DM patients had a significantly larger %NC (17.8 ± 5.6% vs. 12.5 ± 6.1%, p = 0.003) compared with non-DM patients; and MS patients had a significantly larger %NC (17.3 ± 5.8% vs. 12.8 ± 6.2%, p = 0.016) as compared to non-MS patients. Finally, VH-IVUS-derived thin-cap fibroatheromas were more frequent in DM patients (3.4 ± 2.0 vs. 2.1 ± 1.7 in non-DM patients, p = 0.016) and in MS patients (4.1 ± 2.1 vs. 1.9 ± 1.4 in non-MS patients, p = 0.001). Three-vessel VH-IVUS analysis showed that DM and MS patients, compared to patients without DM or MS, had a larger plaque-plus-media burden, larger amount of NC, and more frequent VH-IVUS-derived thin-cap fibroatheromas in coronary arterial trees, implying greater plaque vulnerability in DM and MS patients.

Tissue factor pathway inhibitor-2 is downregulated by ox-LDL and inhibits ox-LDL induced vascular smooth muscle cells proliferation and migration

Introduction Tissue factor pathway inhibitor-2 (TFPI-2) is a member of the Kunitz-type family of serine protease inhibitors, which inhibits several matrix metalloproteinases activity involved in extracellular matrix degradation. Studies have shown low TFPI-2 expression in the shoulder regions of atherosclerotic plaques. But studies evaluating its role in the progression of atherosclerotic plaque are scarce. Vascular smooth muscle cells (VSMCs) are important components of atherosclerotic plaques and oxidized low density lipoprotein (ox-LDL) is an important detrimental factor of atherosclerosis. The aim of this study is to elucidate the effect of TFPI-2 on smooth muscle cell proliferation and migration induced by ox-LDL. Methods Retroviruses expressing human TFPI-2 were constructed. Cell proliferation was determined by CCK-8 assay. Cell apoptosis was analyzed by double staining of FITC-Annexin V and propidium iodide. Cell migration was studied through a Transwell chamber and with a scratch-wound assay. The matrix metalloproteinase-2 and − 9 activities were analyzed by gelatin zymography. Phosphorylation of FAK was analyzed by western blot. Results TFPI-2 over-expression of mRNA and protein was confirmed in infected cells. CCK-8 assay showed that TFPI-2 inhibit VSMCs proliferation induced by ox-LDL while without cytotoxicity to VSMCs. Transwell and scratch wound assay confirmed TFPI-2 over-expression can inhibit VSMC migration. Zymography assay showed that TFPI-2 can inhibit MMP-2, 9 activity induced by ox-LDL. Western blot assay showed TFPI-2 can inhibit cyclinD1 expression and FAK phosphorylation. Conclusion TFPI-2 over-expression may strongly inhibit the proliferation and migration of VSMCs and suppresses MMP-2, 9 activity induced by ox-LDL, making it a promising candidate for treatment of atherosclerotic process.

Changes in atherosclerotic plaques induced by inhalation of diesel exhaust

ObjectiveExposure to particulate matter air pollution may be an independent risk factor for cardiovascular morbidity and mortality; however, the biological mechanisms are unclear. We hypothesize that exposure to diesel exhaust (DE), an important source of traffic-related particulate air pollution, promotes changes of atherosclerotic plaque component that may lead to plaque vulnerability. Methods and results30-week old ApoE knockout mice fed with regular chow inhaled DE (at 200μg/m3 of particulate) or filtered-air (control) for 7 weeks (6h/day, 5 days/week) (12mice/group). Total number of alveolar macrophages (p<0.01) and alveolar macrophages positive for particles (p<0.0001) were more than 8-fold higher after DE inhalation than the control. DE inhalation caused 1.5 to 3-fold increases in plaque lipid content (p<0.02), cellularity (p<0.02), foam cell formation (p<0.04), and smooth muscle cell content (p<0.05). The expression of oxidative stress markers, iNOS, CD36, and nitrotyrosine was significantly increased by 1.5 to 2-fold in plaques, with enhanced systemic lipid and DNA oxidation (p<0.02). Increased foam cells and the expression of iNOS (R2=0.72, p=0.0081) and CD36 (R2=0.49, p=0.015) in plaques were positively correlated with the magnitude of DE exposure. ConclusionsExposure to DE promotes changes in atherosclerotic plaques characteristic of unstable vulnerable plaques. Increased systemic and plaque oxidative stress markers suggest that these changes in plaques could be due to DE-induced oxidative stress.

Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy

Several studies have suggested that evolving mechanical stresses and strains drive atherosclerotic plaque development and vulnerability. Especially, stress distribution in the plaque fibrous capsule is an important determinant for the risk of vulnerable plaque rupture. Knowledge of the stiffness of atherosclerotic plaque components is therefore of critical importance. In this work, force mapping experiments using atomic force microscopy (AFM) were conducted in apolipoprotein E-deficient (ApoE(-/-)) mouse, which represents the most widely used experimental model for studying mechanisms underlying the development of atherosclerotic lesions. To obtain the elastic material properties of fibrous caps and lipidic cores of atherosclerotic plaques, serial cross-sections of aortic arch lesions were probed at different sites. Atherosclerotic plaque sub-structures were subdivided into cellular fibrotic, hypocellular fibrotic and lipidic rich areas according to histological staining. Hertz's contact mechanics were used to determine elasticity (Young's) moduli that were related to the underlying histological plaque structure. Cellular fibrotic regions exhibit a mean Young modulus of 10.4±5.7kPa. Hypocellular fibrous caps were almost six-times stiffer, with average modulus value of 59.4±47.4kPa, locally rising up to ∼250kPa. Lipid rich areas exhibit a rather large range of Young's moduli, with average value of 5.5±3.5kPa. Such precise quantification of plaque stiffness heterogeneity will allow investigators to have prospectively a better monitoring of atherosclerotic disease evolution, including arterial wall remodeling and plaque rupture, in response to mechanical constraints imposed by vascular shear stress and blood pressure.

PLACD-7T Study: Atherosclerotic Carotid Plaque Components Correlated with Cerebral Damage at 7 Tesla Magnetic Resonance Imaging

Introduction:In patients with carotid artery stenosis histological plaque composition is associated with plaque stability and with presenting symptomatology. Preferentially, plaque vulnerability should be taken into account in pre-operative work-up of patients with severe carotid artery stenosis. However, currently no appropriate and conclusive (non-) invasive technique to differentiate between the high and low risk carotid artery plaque in vivo is available. We propose that 7 Tesla human high resolution MRI scanning will visualize carotid plaque characteristics more precisely and will enable correlation of these specific components with cerebral damage.Study objective:The aim of the PlaCD-7T study is 1: to correlate 7T imaging with carotid plaque histology (gold standard); and 2: to correlate plaque characteristics with cerebral damage ((clinically silent) cerebral (micro) infarcts or bleeds) on 7 Tesla high resolution (HR) MRI.Design:We propose a single center prospective study for either symptomatic or asymptomatic patients with haemodynamic significant (70%) stenosis of at least one of the carotid arteries. The Athero-Express (AE) biobank histological analysis will be derived according to standard protocol. Patients included in the AE and our prospective study will undergo a pre-operative 7 Tesla HR-MRI scan of both the head and neck area.Discussion:We hypothesize that the 7 Tesla MRI scanner will allow early identification of high risk carotid plaques being associated with micro infarcted cerebral areas, and will thus be able to identify patients with a high risk of periprocedural stroke, by identification of surrogate measures of increased cardiovascular risk.

GPR92/LPA5 lysophosphatidate receptor mediates megakaryocytic cell shape change induced by human atherosclerotic plaques

AimsOxidative processes and vascular inflammation underlying atherosclerosis lead to an accumulation of lysophosphatidic acid (LPA) molecules in the atheromatous intima. LPA, a platelet-activating component of human atherosclerotic plaques, possibly contributes to atherothrombus formation after plaque rupture. Human platelets express mRNA for the G protein-coupled receptors LPA1–7 that derive from megakaryocytes. The aim of our study was to identify the functional LPA receptor(s) in human platelets by silencing individual LPA receptors in megakaryocytic (MK) cells.Methods and resultsWe studied shape change of two human MK cell lines (Meg-01, Dami) by turbidometry, phase-contrast and scanning electron microscopy. They showed upon LPA stimulation a rapid, Rho-kinase-mediated shape change similar to that of human platelets. By qRT–PCR analysis we found expression of LPA1–7 in both cell lines; LPA4 and LPA5 were the most abundant receptor transcripts. In both Meg-01 and Dami cells, the rank order of activation by LPA species was similar to that found in platelets: alkyl-LPA 18:1 > alkyl-LPA 16:0 > acyl-LPA 18:1 >> alkyl-LPA 18:0. Knock-down of individual LPA receptors by siRNA showed that LPA-mediated activation of MK cells was mediated by LPA5, but not by LPA1–4,6,7. Importantly, we found that human atherosclerotic plaque and lipid-rich core induced shape change of Dami cells, and that this effect was inhibited after LPA5 silencing.ConclusionsOur findings indicate that LPA5 mediates LPA-induced shape change of MK cells and support its involvement in atherosclerotic plaque and lipid-rich core-mediated platelet activation. This receptor could be an attractive novel target for antithrombotic therapy.

Sensitivity Analysis of Plaque Components within Arterial Wall Simulations

AbstractIn this contribution we focus on a sensitivity analysis of arterial wall simulations with respect to atherosclerotic plaque components. For the simulations we use patient specific arterial wall geometries gained from medical imaging techniques. The technique used here is the Intravascular Ultra Sound Virtual Histology (IVUS‐VH). The resulting discretization is used for the simulation of a diseased artery with plaque components. The material parameters for the arterial layers are based on uniaxial tension tests, whereas the plaque parameters are chosen in a physiologically suitable range. One final goal is to study the sensitivity of the resulting deformation and stress distribution in the arterial wall with respect to the variation of the material parameters of the plaque. (© 2010 Wiley‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

Blood-born tissue factor in cardiovascular disease: where are we now?

Over the last decade, many clinical, pathological and laboratory data have been obtained indicating that, in the majority of cases, acute coronary thrombosis occurs upon rupture of the thin fibrous cap of a vulnerable atherosclerotic plaques, a result of a series of immuno-inflammatory processes. The inner content of the plaque becomes then exposed to the circulating blood leading to the deposition of thrombotic material into the lumen [1]. Our data, as well as that acquired by others, demonstrate that one of the major determinants of the thrombogenicity of the disrupted atheroma is tissue factor (TF),which triggers the activation of coagulation by binding to factor VII/VIIa. TF is particularly abundant in the lipid-rich necrotic core of the lesion, which is therefore the most thrombogenic component of atherosclerotic plaque [2]. The binding of TF to factor VIIa causes thrombin generation, which in turn induces platelet activation and fibrin formation leading to a partial or total thrombotic occlusion of the artery, and to the occurrence of an acute coronary syndrome (ACS) [1]. We also have demonstrated that the activation of the coagulation cascade within the coronary vessel at sites of atherosclerotic plaque rupture is largely TF-dependent, since a significant reduction in both platelet and fibrin deposition can be obtained by local pretreatment of atherosclerotic lesions with the recombinant analog of the physiologic tissue factor pathway inhibitor (rTFPI) or with a specific anti-TF antibody [3]. Instabilization and rupture of the plaque are mainly due to inflammatory processes that take place in the vessel wall. Experimental studies demonstrate that inflammatory cells such as macrophages, macrophage-derived lipid laden ‘foam cells’, and T lymphocytes are major constituents of plaques, and infiltrate areas of superficial erosion and the shoulder region of the coronary lesions where the fibrous cap usually breaks [4]. Macrophages and ‘foam cells’ are also the major source of TF within the lesions, and therefore this protein can be considered a product of the inflammatory processes of the atheroma [1]. The interplay between these cells results in the production and local secretion of several inflammatory cytokines and chemokines like interleukin (IL)-1, interferon-c and TNF-a, which, in turn, lead to the release of metalloproteinases (MMPs), particularly of MMP-9, which degrade extracellular matrix and particularly collagen, thus inducing plaque weakening and fracture[1, 5, 6].

Establishment and Characterization of an Experimental Model of Coronary Thrombotic Microembolism in Rats

To establish a model of coronary thrombotic microembolism in rats, either automicrothrombotic particulates (CM group) or saline control (SHAM group) was injected into temporarily clamped aortas of male Sprague-Dawley rats. After automicrothrombotic particulate injection, serum c-troponin I and von Willebrand factor levels, the no-flow area as evaluated by Thioflavin S, myocardial leukocyte infiltration levels, myocardial expressions of tumor necrosis factor alpha and interleukin-6, the percentage of arterioles obstructed by thrombosis, and myocardial fibrosis were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the sham group. Thus, aortic automicrothrombotic particulate injection could induce coronary microembolism in rats, and this model could be of value in improving the understanding of pathophysiology of coronary microembolism.

SCAVENGER RECEPTOR-MEDIATED TARGETING OF MACROPHAGE FOAM CELLS IN ATHEROSCLEROTIC PLAQUE USING OLIGONUCLEOTIDE-FUNCTIONALIZED NANOPARTICLES

Macrophage foam cells are key components of atherosclerotic plaque and play an important role in the progression of atherosclerosis leading to plaque rupture and thrombosis. Foam cells are emerging as attractive targets for therapeutic intervention and for imaging the progression of disease. Therefore, designing nanoparticles (NPs) targeted to macrophage foam cells in plaque is of considerable therapeutic significance. Here we report the construction of an oligonucleotide functionalized NP system with high affinity for foam cells. Nanoparticles functionalized with a 23-mer poly-Guanine (polyG) oligonucleotide are specifically recognized by the scavenger receptors on lipid-laden foam cells in vitro and ex vivo. The enhanced uptake of polyG-functionalized NPs by foam cells is inhibited in the presence of acetylated-LDL, a known ligand of scavenger receptors. Since polyG oligonucleotides are stable in serum and are unlikely to induce an immune response, their use for scavenger receptor-mediated targeting of macrophage foam cells provides a strategy for targeting atherosclerotic lesions.

Atherosclerotic plaque components characterization and macrophage infiltration identification by intravascular ultrasound elastography based on b-mode analysis: validation in vivo

Intravascular ultrasound elastography (IVUSE) is a promising imaging technique for early investigation of vulnerable plaques. Compared to radiofrequency signal processing, digital B-mode analysis is simple and of higher portability. However, rare studies have been reported validating the latter technique in vivo. In this study, we developed an IVUSE computer software system involving semi-automatic border delineation and block-matching algorithm and validated the system in vivo. Seven minipigs were fed with atherogenic diet for 40weeks. For each pig, the endothelium of one side of the renal arteries was denuded at the fifth week. With cross-correlation analysis, Lagrangian strain was calculated from two intravascular ultrasound images acquired in situ. Sixty regions of interests were selected from 35 elastograms matched well with the corresponding histological slices. Plaque types within these regions were classified as fibrous, fibro-fatty or fatty on Masson's trichrome and Oil-red O staining. Macrophage infiltration was also evaluated with immunohistology. Comparison between the mean strain value of the region of interest and the histological results revealed significant differences in strain values among different plaque types and non-diseased artery walls. The extent of macrophage infiltration was found to be correlated positively with strain values. For identification of fibro-fatty and fibrous plaques and macrophage infiltration, the system showed high sensitivity (93, 96 and 92%, respectively) and specificity (89, 76 and 66%, respectively), as revealed by receiver operating characteristic analysis. Our IVUSE system based on B-mode analysis is capable of characterizing fibrous and fibro-fatty plaques and macrophage intensity, thus holds potential for identifying vulnerable plaque.

Three-dimensional registration of histology of human atherosclerotic carotid plaques to in-vivo imaging

An accurate spatial relationship between 3D in-vivo carotid plaque and lumen imaging and histological cross sections is required to study the relationship between biomechanical parameters and atherosclerotic plaque components. We present and evaluate a fully three-dimensional approach for this registration problem, which accounts for deformations that occur during the processing of the specimens. By using additional imaging steps during tissue processing and semi-automated non-linear registration techniques, a 3D-reconstruction of the histology is obtained. The methodology was evaluated on five specimens obtained from patients, operated for severe atherosclerosis in the carotid bifurcation. In more than 80% of the histology slices, the quality of the semi-automated registration with computed tomography angiography (CTA) was equal to or better than the manual registration. The inter-observer variability was between one and two in-vivo CT voxels and was equal to the manual inter-observer variability. Our technique showed that the angles between the normals of the registered histology slices and the in-vivo CTA scan direction ranged 6–56°, indicating that proper 3D-registration is crucial for establishing a correct spatial relation with in-vivo imaging modalities. This new 3D-reconstruction technique of atherosclerotic plaque tissue opens new avenues in the field of biomechanics as well as in the field of image processing, where it can be used for validation purposes of segmentation algorithms.

Phase-sensitive black-blood coronary vessel wall imaging

Black-blood MR coronary vessel wall imaging may become a powerful tool for the quantitative and noninvasive assessment of atherosclerosis and positive arterial remodeling. Although dual-inversion recovery is currently the gold standard, optimal lumen-to-vessel wall contrast is sometimes difficult to obtain, and the time window available for imaging is limited due to competing requirements between blood signal nulling time and period of minimal myocardial motion. Further, atherosclerosis is a spatially heterogeneous disease, and imaging at multiple anatomic levels of the coronary circulation is mandatory. However, this requirement of enhanced volumetric coverage comes at the expense of scanning time. Phase-sensitive inversion recovery has shown to be very valuable for enhancing tissue-tissue contrast and for making inversion recovery imaging less sensitive to tissue signal nulling time. This work enables multislice black-blood coronary vessel wall imaging in a single breath hold by extending phase-sensitive inversion recovery to phase-sensitive dual-inversion recovery, by combining it with spiral imaging and yet relaxing constraints related to blood signal nulling time and period of minimal myocardial motion.

Short Communication: Dating Components of Human Atherosclerotic Plaques

Atherosclerotic plaques that give rise to acute clinical symptoms are typically characterized by degradation of the connective tissue and plaque rupture. Experimental studies have shown that mechanisms to repair vulnerable lesions exist, but the rate of remodeling of human plaque tissue has not been studied. In the present study, we determined the biological age of different components of advanced human atherosclerotic plaques by analyzing tissue levels of (14)C released into the atmosphere during the nuclear weapons tests in the late 1950s and early 1960s. Atherosclerotic plaques were obtained from 10 patients (age 46 to 80 years) undergoing carotid surgery. Different regions of the plaques were dissected and analyzed for (14)C content using accelerator mass spectrometry. At the time of surgery, the mean biological age of the cap region was 6.4+/-3.2 years, which was significantly lower than that of the shoulder region (12.9+/-3.0 years, P<0.01), the interface toward the media (12.4+/-3.3 years, P<0.01), and the core (9.8+/-4.5 years, P<0.05). Analysis of proliferative activity and rate of apoptosis showed no signs of increased cellular turnover in the cap, suggesting that the lower (14)C content reflected a more recent time of formation. These results show that the turnover time of human plaque tissue is very long and may explain why regression of atherosclerotic plaque size rarely is observed in cardiovascular intervention trials.

Detection of in vivo atherosclerotic plaque progression with a fibrin-targeted MR contrast agent

Introduction Molecular MRI has emerged as a promising, non-invasive modality to accurately detect high-risk atherosclerotic plaques. Due to the inherently low sensitivity of MRI, contrast agents targeted at an abundant and robust component of the lesion are required. Fibrin represents a clinically relevant target and imaging of aortic, coronary, carotid and cardiac thrombi have been demonstrated both in animal models and men. It has been recognised as an important component of atherosclerotic plaques and is present throughout plaque development.

Optical coherence tomography imaging: current status and future perspectives

Optical coherence tomography (OCT) is an optical analogue of intravascular ultrasound that provides high-resolution (10-20μm) cross-sectional images of coronary arteries. The micron-scale resolution of OCT has an ability to capture in vivo what was previously seen only through a pathologist's microscope. OCT can differentiate three types of atherosclerotic plaque components (fibrous, fibrocalcific and lipid-rich) with high sensitivity and specificity. Early in vitro and in vivo studies have demonstrated a possibility of OCT for identifying vulnerable plaque features, in particular the quantification of plaque rupture, intracoronary thrombus, thin-capped fibroatheroma and the distribution of macrophages within the fibrous cap. In addition, OCT has shown its effectiveness in imaging the short-term and long-term results of percutaneous coronary intervention. OCT can precisely assess stent strut malapposition, tissue protrusion, coronary artery dissection, and neointimal hyperplasia following stent implantation. Recently, next-generation OCT, called Fourier-domain OCT, has already been shown to be a powerful enabling technology for coronary imaging. The novel developments with high frame rate and fast pullback speed simplifies procedural requirements and will eventually eliminate limitations of current OCT systems such as need for proximal vessel balloon occlusion during image acquisition. This report details current and future developments in OCT imaging, which include exciting technological advancements that will consolidate the position of OCT as a key diagnostic tool to complement the armamentarium of the cardiologist well into the future.

Adiponectin Inhibits Lipopolysaccharide-Induced Adventitial Fibroblast Migration and Transition to Myofibroblasts via AdipoR1-AMPK-iNOS Pathway

Adiponectin is an important antiatherogenic adipocytokine that inhibits inflammation, insulin resistance, and oxide stress. Inflammation in the vascular adventitia is a crucial factor in the pathogenesis of atherosclerosis. Adventitial fibroblasts (AFs) can proliferate, divide into myofibroblasts, and migrate to the intima to become a new component of atherosclerotic plaque under inflammation and atherosclerosis. We investigated whether adiponectin might prevent AFs from proliferating, migrating, and transforming into myofibroblasts. Cultured AFs were stimulated with lipopolysaccharide (LPS) in the presence or absence of adiponectin. Methyl thiazolyl tetrazolium assay and migration and scratch-wound assays demonstrated that adiponectin reduced the AF proliferation and migration induced by LPS, respectively, whereas treatment with AdipoR1 small interfering (si) RNA (siAdipoR1), AMP-activated protein kinase (AMPK) siRNA (siAMPK), and an AMPK inhibitor reversed the effect. Immunocytochemistry and Western blot revealed that adiponectin reduced the transition of AFs to myofibroblasts, and treatment with siAdipoR1, siAMPK, and the AMPK inhibitor increased the transition. RT-PCR, Western blotting, and nitric oxide (NO) assay showed that adiponectin reduces induced NO synthase (iNOS) and nitrotyrosine expression and NO and ONOO(-) production induced by LPS. Treatment with siAdipoR1, siAMPK, and the AMPK inhibitor significantly attenuated adiponectin-induced phosphorylation of AMPK and its downstream target acetyl-coenzyme A carboxylase and up-regulated iNOS mRNA and protein expression, which resulted in a marked increase of NO and ONOO(-) production. In apolipoprotein E-deficient mice, immunohistochemistry of treated vascular adventitia showed that both iNOS expression and ONOO(-) production could be reversed with an adenovirus-adiponectin vector. Taken together, these results suggest that adiponectin reduces LPS-induced NO production and nitrosative stress and prevents AFs from proliferating, transforming to myoflbroblasts, and migrating to the intima, thus worsening atherosclerosis, by inhibiting the AdipoR1-AMPK-iNOS pathway in AFs.

Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis.

Deletion of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Vascular smooth muscle cells (VSMCs) are an important component of atherosclerotic plaques, responsible for promoting plaque stability in advanced lesions. Fibrous caps of unstable plaques contain less collagen and ECM components and fewer VSMCs than caps from stable lesions. Here, we investigated the role of Akt1 in VSMC proliferation, migration, and oxidative stress-induced apoptosis. In addition, we also characterized the atherosclerotic plaque morphology and cardiac function in an atherosclerosis-prone mouse model deficient in Akt1. Absence of Akt1 reduces VSMC proliferation and migration. Mechanistically, the proliferation and migratory phenotype found in Akt1-null VSMCs was linked to reduced Rac-1 activity and MMP-2 secretion. Serum starvation and stress-induced apoptosis was enhanced in Akt1 null VSMCs as determined by flow cytometry using Annexin V/PI staining. Immunohistochemical analysis of atherosclerotic plaques from Akt1(-/-ApoE-/-) mice showed a dramatic increase in plaque vulnerability characteristics such as enlarged necrotic core and reduced fibrous cap and collagen content. Finally, we show evidence of myocardial infarcts and cardiac dysfunction in Akt1(-/-ApoE-/-) mice analyzed by immunohistochemistry and echocardiography, respectively. Akt1 is essential for VSMC proliferation, migration, and protection against oxidative stress-induced apoptosis. Absence of Akt1 induces features of plaque vulnerability and cardiac dysfunction in a mouse model of atherosclerosis.

Flat Panel Volume Computed Tomography of the Coronary Arteries

Multidetector-row computed tomography (MDCT) has evolved into a sensitive diagnostic tool for the noninvasive detection of coronary artery stenosis, but remains limited by spatial resolution. Flat panel volume computed tomography (fpVCT) offers a higher spatial resolution. In a postmortem investigation of autopsy specimens, the accuracies of fpVCT for measuring the severity of coronary artery stenosis and the size of atherosclerotic plaque components were determined. In 25 autopsy cases, hearts were isolated, the left anterior descending coronary arteries filled with contrast agent, and depicted with a prototype fpVCT unit with a slice thickness of 0.25 mm. Transections of the left anterior descending coronary arteries were reconstructed and compared with histopathologic sections using light microscopy. FpVCT measurements of luminal stenosis (r = 0.81), total plaque area (r = 0.88), calcified plaque area (r = 0.92), noncalcified plaque area (r = 0.83), and lipid core size (r = 0.67; P < .02) correlated well with histopathology (P < .0001). The limits of agreement for measuring any plaque component were three times smaller than those reported for MDCT. Postmortem coronary fpVCT provides an accurate and reproducible method for the quantitative assessment of both luminal stenosis and atherosclerotic plaque size. Because of its high spatial resolution, the method should be sufficiently accurate to reliably detect the lipid pools of vulnerable plaques.

The role of oxidized low-density lipoprotein in the activation of peroxisome proliferator-activated receptor gamma: implications for atherosclerosis.

A molecular mechanism has been discovered that helps explain the formation of foam cells, which are components of atherosclerotic plaque. It involves the stimulation by oxidized low-density lipoprotein of its own uptake into macrophages through activation of the peroxisome proliferator-activated receptor gamma.